Jia Jianwu, Wang Jing, Yin Meifeng, Liu Yongdong
Department of Neurosurgery, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People's Republic of China.
Department of Pediatrics, Weifang People's Hospital, Weifang, Shandong 261041, People's Republic of China.
Onco Targets Ther. 2019 Jul 8;12:5437-5448. doi: 10.2147/OTT.S213026. eCollection 2019.
Aberrant microRNA (miRNA) expression has been widely reported to play a crucial role in the progression and development of glioblastoma (GBM). miR-605 has been identified as a tumor-suppressing miRNA in several types of human cancers. Nevertheless, the expression profile and detailed roles of miR-605 in GBM remain unclear and need to be further elucidated.
RT-qPCR analysis was utilized for the determination of miR-605 expression in GBM tissues and cell lines. In addition, CCK-8 assay, transwell migration and invasion assays, as well as sub-cutaneous xenograft mouse models were utilized to evaluate the effects of miR-605 upregulation in GBM cells. Notably, the potential mechanisms underlying the activity of miR-605 in the malignant phenotypes of GBM were explored.
We observed that expression of miR-605 was reduced in GBM tissues and cell lines. Decreased miR-605 expression exhibited significant correlation with KPS score. The overall survival rate in GBM patients with low miR-605 expression was lower than that of patients with high miR-605 expression. Increased miR-605 expression suppressed the proliferation, migration, and invasion of U251 and T98 cells. In addition, miR-605 upregulation impaired tumor growth in vivo. Furthermore, SRY-Box 9 (SOX9) was identified as a direct target gene of miR-605 in U251 and T98 cells. SOX9 expression was shown to exhibit an inverse correlation with miR-605 expression in GBM tissues. Moreover, silencing of SOX9 expression mimicked the tumor-suppressing roles of miR-605 in U251 and T98 cells, while SOX9 restoration rescued the suppressive effects of miR-605 overexpression in the same. Notably, miR-605 suppressed the PI3K/Akt pathway in GBM in vitro and in vivo.
These results demonstrated that miR-605 acts as a tumor suppressor in the development of GBM by directly targeting SOX9 and inhibiting the activation of the PI3K/Akt pathway, suggesting its potential role as a therapeutic target for GBM.
异常的微小RNA（miRNA）表达在胶质母细胞瘤（GBM）的进展和发展中起着关键作用，这一点已被广泛报道。miR-605已被确定为几种人类癌症中的一种肿瘤抑制性miRNA。然而，miR-605在GBM中的表达谱和详细作用仍不清楚，需要进一步阐明。
采用逆转录定量聚合酶链反应（RT-qPCR）分析来测定GBM组织和细胞系中miR-605的表达。此外，利用细胞计数试剂盒-8（CCK-8）检测、Transwell迁移和侵袭检测以及皮下异种移植小鼠模型来评估miR-605上调对GBM细胞的影响。值得注意的是，还探索了miR-605在GBM恶性表型中发挥作用的潜在机制。
我们观察到miR-605在GBM组织和细胞系中的表达降低。miR-605表达降低与卡氏功能状态（KPS）评分显著相关。miR-605低表达的GBM患者的总生存率低于miR-605高表达的患者。miR-605表达增加抑制了U251和T98细胞的增殖、迁移和侵袭。此外，miR-605上调损害了体内肿瘤生长。此外，性别决定区Y框蛋白9（SOX9）被确定为U251和T98细胞中miR-605的直接靶基因。在GBM组织中，SOX9表达与miR-605表达呈负相关。此外，沉默SOX9表达模拟了miR-605在U251和T98细胞中的肿瘤抑制作用，而恢复SOX9则挽救了miR-605过表达在相同细胞中的抑制作用。值得注意的是，miR-605在体外和体内均抑制了GBM中的磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）信号通路。
这些结果表明，miR-605通过直接靶向SOX9并抑制PI3K/Akt信号通路的激活，在GBM的发展中发挥肿瘤抑制作用，提示其作为GBM治疗靶点的潜在作用。
